Browsing by Tema "AAA proteins"

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    Author response: Specific proteolysis mediated by a p97-directed proteolysis-targeting chimera (p97-PROTAC)
    (2025) Constanza Salinas-Rebolledo; Javier Blesa; Guillermo Valenzuela-Nieto; David Schwefel; Natalia López-González del Rey; Maxs Méndez-Ruette; Janine Burkhalter; Elizabeth Carrazana; Francisca Díaz-Tejeda; Ignacio Arias Catalán
    Synthetic adaptors combining camelid nanobodies with the UBX domain of the p97 adaptor FAF1 enable targeted substrate delivery to p97, establishing an E3 ubiquitin ligase-independent mechanism for selective protein degradation.
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    Specific proteolysis mediated by a p97-directed proteolysis-targeting chimera (p97-PROTAC)
    (eLife Sciences Publications Ltd, 2025) Constanza Salinas-Rebolledo; Javier Blesa; Guillermo Valenzuela; David Schwefel; Natalia López‐González del Rey; Maxs Méndez-Ruette; Janine Burkhalter; Elizabeth Carrazana; Francisca Díaz-Tejeda; Ignacio Pérez Catalán
    The p97 protein is a member of the AAA+ family of ATPases. This protein is encoded by the <i>VCP</i> gene. It is a mechanoenzyme that uses energy from ATP hydrolysis to promote protein unfolding and segregation actively. The unfolded products are subsequently presented to the 26S proteasome for degradation. p97 substrate recognition is mediated by adaptors, which interact with substrates directly or indirectly through ubiquitin modifications, resulting in substrate funnelling into the central pore of the p97 hexamer and unfolding. Here, we engineered synthetic adaptors to target specific substrates to p97, using the extraordinary intracellular binding capabilities of camelid nanobodies fused to the UBX domain of the p97 adaptor protein Fas-associated factor-1 (FAF1). In such a way, we created a p97-directed proteolysis-targeting chimera (PROTAC), representing a novel and unique E3 ubiquitin ligase-independent strategy to promote specific proteolysis. All functional assays were performed in human cell lines to evaluate the system's efficacy and specificity in a physiologically relevant context.
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    Specific proteolysis mediated by a p97-directed proteolysis-targeting chimera (PROTAC)
    (2024) Constanza Salinas-Rebolledo; Javier Blesa; Guillermo Valenzuela; David Schwefel; Natalia López‐González del Rey; Maxs Méndez-Ruette; Janine Burkhalter; Luis Federico Bátiz; Ronald Jara; José Á. Obeso
    Abstract The p97 protein is a member of the AAA + family of ATPases. It is a mechanoenzyme that uses energy from ATP hydrolysis to promote protein unfolding and segregation actively. The unfolded products of p97 are presented to the 26S Proteasome for degradation. p97 substrate recognition is mediated by adaptors, which interact with substrates directly or indirectly through ubiquitin modifications, resulting in substrate funnelling into the central pore of the p97 hexamer and unfolding. We have engineered synthetic adaptors to target specific substrates to p97, using the extraordinary intracellular binding capabilities of camelid nanobodies fused to the UBX domain of the p97 Adapter FAF1. In such a way, we created a p97-directed proteolysis-targeting chimera (PROTAC), representing a unique E3 ubiquitin ligase-independent strategy to promote specific proteolysis.